Hypoxia-inducible factors are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-α) and a constitutive nuclear beta subunit (HIF-β). The alpha subunit is the regulatory subunit specific to the oxygen response pathway, and can be one of three subunits, HIF1α, 2α or 3α (HIF-1 α, HIF-2 α and HIF-3α, respectively) (Maxwell et al., Curr. Opin. Genet. Dev., 11:293-299 (2001); Safran and Kaelin, J. Clin. Invest., 111:779-783 (2003)).
Hypoxia-inducible factor-1 (HIF1) is a heterodimer composed of a 120 kDa alpha subunit complexed with a 91 to 94 kDa beta subunit, both of which contain a basic helix-loop-helix (Wang and Semenza, J. Biol. Chem., 270:1230-1237 (1995)). The gene encoding hypoxia-inducible factor-1 alpha (HIF1-alpha, also called HIF-1 alpha, HIF-1A, HIF-1A, HIF1-A, and MOP1) was cloned in 1995 (Wang et al., Proc. Natl. Acad. Sci. U.S.A., 92:5510-5514 (1995)).
Hypoxia inducible factors (HIFs), are essential regulators and mediators of the cellular oxygen-signaling pathway and are important for maintaining cellular oxygen homeostasis. (See., e.g., Rankin, et al., Cell Death and Diff, 12:678-685 (2008)). Hypoxia induces the expression of genes participating in many cellular and physiological processes, including oxygen transport and iron metabolism, erythropoiesis, angiogenesis, glycolysis, glucose uptake, transcription, metabolism, pH regulation, growth-factor signaling, response to stress and cell adhesion. Hypoxia-induced pathways, in addition to being required for normal cellular processes, can also aid tumor growth by allowing or aiding angiogenesis, immortalization, genetic instability, tissue invasion and metastasis (Harris, Nat. Rev. Cancer, 2:38-47 (2002)); Maxwell et al., Curr. Opin. Genet. Dev., 11:293-299 (2001)).
As oxygen homeostasis is essential to both cellular and systemic functions, cellular and systemic oxygen concentrations are tightly regulated via response pathways that affect the activity and expression of a multitude of cellular proteins. This balance is disrupted in a variety of diseases, including heart disease, cancer, cerebrovascular disease, and chronic obstructive pulmonary disease (Semenza et al., Genes Dev., 14: 1983-1991 (2000); Semenza et al., Trends Mol. Med., 7:345-350 (2001)). Cellular changes can include an increase in glycolysis and an increase in production of angiogenic factors. In fact, some tumor cells undergo adaptive mutations that allow them to proliferate even under hypoxic conditions. Hypoxia in tumors can be further associated with resistance to radiotherapies and chemotherapies, and thus can be an indicator of poor survival.
Glucose transporter 1 (GLUT1), also known as solute carrier family 2 (SLCA2) or facilitated glucose transporter member 1 (SLC2A1) is a 492 amino acid protein (NCBI accession numbers NP—006507.2 or P11166.2). GLUT1 is a member of a small family 45-55 kDa hexose transport proteins and is invovled in facilitating the transport of glucose across the plasma membranes of mammalian cells. (See, e.g., Doege et al., Biochem J., 15:(359):443-449 (2001); Mueckler, et al., Science 229(4717):941-945(1985); and Olsen et al., Annual Review of Nutrition, 16:235-256 (1996)).
An important aspect of personalized medicine is the identification of targeted therapies useful in the treatment of difficult to treat diseases. Such therapies are particularly important in cancer, where the goal is to preferentially inhibit the growth and proliferation of tumor cells while leaving normal cells unaffected. The ability to treat individual patients with specific therapies is becoming increasingly important to those being treated as well as to those administering the treatments. Physicians, patients, and third-party payers all seek therapies tailored to the individual needs of the patient.